© 2005 The Japanese Biochemical Society
BIOCHEMISTRY |
X-Linked Inhibitor of Apoptosis Functions as Ubiquitin Ligase toward Mature Caspase-9 and Cytosolic Smac/DIABLO
1 Division of Molecular Biology, School of Life Science, Tokyo University of Pharmacy, and Life Science 1432-1 Horinouchi, Hachioji, Tokyo 192-0392; and 2 Division of Bioscience, the Central Laboratory, Nippon Flour Mills Co., Ltd., 5-1-3 Midorigaoka, Atsugi, Kanagawa 243-0041
3 To whom correspondence should be addressed. Tel: +81-46-222-6948, Fax: +81-46-221-4970, E-mail: h-yasuda{at}yk9.so-net.ne.jp
Members of the IAP (inhibitor of apoptosis) family function as anti-apoptotic proteins by binding directly to caspase-3, -7, and -9 to inhibit their activities. During apoptosis, the activities of IAPs are relieved by a second mitochondria-derived caspase activator, named Smac/DIABLO. Some IAPs have a C-terminal RING finger domain that has been identified as the essential motif for the activity of ubiquitin ligase (E3). Here we show that X-linked IAP (XIAP) mediates the polyubiquitination of caspase-9 and Smac. The large subunit of mature caspase-9 was polyubiquitinated by XIAP in vitro, while procaspase-9 was not. Furthermore, the polyubiquitinated form of caspase-9 accumulated in an XIAP-dependent manner in intact cells. The ubiquitination of caspase-9 was significantly inhibited in the presence of mature Smac, whereas XIAP was also found to promote the polyubiquitination of cytosolic Smac both in vitro and in intact cells. These ubiquitination reactions require the RING finger domain of XIAP. These findings suggest that XIAP functions as ubiquitin ligase toward mature caspase-9 and Smac to inhibit apoptosis.
* Present address: Department of Biochemistry, Max-Plank Institute, Germany.
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